Diuretic compositions



United States Patent 3,288,678 DIURETIC COMPOSITIONS George de Stevens and Lincoln Harvey Werner, Summit, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 12, 1963, Ser. No. 308,327 10 Claims. (Cl. 167-65) This application is in part a continuation of application Serial No. 845,623, filed October 12, 1959; which in turn is in part a continuation of application Serial No. 791,831, filed February 9, 1959; which in turn is in part a continuation of application Serial No. 764,482, filed September 29, 1959; which in turn is in part a continuation of application Serial No. 751,620, filed July 29, 1959; which in turn is in part a continuation of application Serial No. 740,582, filed June 9, 1958; which in turn is in part a continuation of application Serial No. 727,- 242, filed April 9, 1958; which in turn is in part a continuation of application Serial No. 718,452, filed March 3, 1958, all of which applications are now abandoned.

This invention relates to and has for its object the provision of compositions (and methods for their preparation), useful in the treatment of hypertension. These compositions contain essentially (1) dihydro benzothiadiazine-1,1-dioxides and (2) an indole alkaloid of the Apocynaceae family, such as reserpine.

One may desirably use about 1 to about 20 percent of the dihydro benZothiadiazine-1,1-dioxide (e.g. 6 chloro-7-sulfamyl-3,4-dihydro 2 H-[1,2,4]-benzothiadiazine-1,1-dioxide or 2-, 3- or 2,3-lower alkyl, such as (1) 2-methyl, (2) 2-ethyl, (3) 3-butyl, (4) 2,3-dirnethyl, (5) 3-isobutyl or (6) 2 or -3-ary1 lower alkyl, such as benzyl, phenethyl, etc., or other such substituted derivatives of 6- chloro 7 snlfamyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,1-dioxide) to about 0.005 to about 0.5 percent of indole alkaloid (e.g. reserpine, deserpidine or rescinnamine). Preferred proportions are about 2.5 to about 10 percent of the dihydro benzothiadiazine-l,l-dioxide to about 0.01 to about 0.04 percent of indole alkaloid (particularly about 2.5 percent benzothiadiazine-1,1- dioxide to about 0.01 percent indole alkaloid).

The tablet, capsule or pill provides a convenient oral form of administration of the compositions of the invention. These forms may be compounded to contain about 10 to about 200 mg. (more particularly about 25 to about 100 mg.) of dihydro benzothiadiazine-l,l-dioxide and about 0.05 to about 5.0 mg. (more particularly about 0.1 to about 0.4 mg.) of reserpine, deserpidine or rescinnamine. Tablets may, of course, be scored to provide for fractional dosages, if desired. Complete tablets (or capsules) containing about 0.1 mg. reserpine or deserpidine or 0.5 mg. rescinnamine and about 25 mg. dihydro benzothiadiazine-l,l-dioxide are convenient for administration and may normally be administrated 13 times daily, but administration may vary with the needs of each particular patient and is best determined by the physician in each case.

The inert fillers and binders which are normally employed in the art of tablet (or capsule) making may be used in formulating tablets (or capsules). Examples of these materials are corn starch, lactose, stearic acid, talc, magnesium stearate, tragacanth, acacia, etc. The quantities of these ingredients may Vary widely in accordance with the dictates of those skilled in the art, and depend "ice largely upon the kind, i.e. soft or hard, and size tablet which is required. Encapsulation may also be eifected, using the same excipients as those used for tablets. At any rate, as has been indicated above, the compounding is effected in exactly the same manner as that normally employed in the art. Any compatible colors, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law, may be used for esthetic purposes or as a means of identification.

The diuretics used in the invention include benzothiadiazine-1,1-dioxides, more particularly, benz-sulfamyl- 3,4-dihydro-2-H-[1,2,4]-benzothiadiazine-1,1-dioxides, in which the nitrogen atom of the sulfamyl group may be unsubstituted or substituted. In addition to the sulfamyl group the carbocyclic portion may contain the radical R which may be hydrogen, lower hydrocarbon, substituted lower hydrocarbon, amino, nitro, etherified hydroxyl, sulfamyl, and particularly halogen. The 3,4- dihydro-2-H-[1,2,4]-benzothiadiaZine-1,l-dioxides of this invention include particularly the benz-N-R '-sulfamyl- 2-R '-3-R -4-R "-3,4-dihydro 2 H-[1,2,4]-benzothiadiazine-1,1-dioxides, in which the carbocyclic portion contains the above-defined radical R and in which R rep resents hydrogen, a hydrocarbon, a substituted hydrocarbon, a hetero-cyclic and a heterocyclic-lower alkyl radical, and each of the radicals R R and R stands for hydrogen, hydrocarbon or substituted hydrocarbon. These compounds may, therefore, be represented by the following formula:

in which R may represent hydrogen, or a hydrocarbon, a substituted hydrocarbon, a heterocyclic or a heterocyclic-lower hydrocarbon radical, each of the radicals R R and R may be hydrogen, hydrocarbon or substituted hydrocarbon and R may stand for lower aliphatic hydrocarbon, halogeno-substituted hydrocarbon and, particularly halogen.

Apart from being hydrogen, R may also stand for aliphatic hydrocarbon radicals, for example, lower aliphatic hydrocarbon, such as lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl and the like, lower alkenyl, e.g. vinyl, l-propenyl and the like, lower alkynyl, e.g. ethinyl and the like, carbocyclic aliphatic hydrocarbons, which contain from three to seven carbon atoms as ring members and in which the carbocyclic portion may be saturated or may contain from one to two double bonds depending on the number of ring carbon atoms, such as cycloalkyl, which contains from five to siX ring carbon atoms, e.g. cyclopentyl or cyclohexyl, or cycloalkenyl, which contains from five to six carbon atoms as ring members, e.g. 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like, or

carbocyclic aliphatic hydrocarbon-lower aliphatic hydrocarbon, primarily carbocyclic alicyclic hydrocarbonlower alkyl, which contains from three to seven carbon atoms as ring members and in which the carbocyclic portion may be saturated or contain from one to two double bonds depending on the number of ring carbon atoms,

and in which lower alkyl represents a lower alkylene radical containing from one to seven, particularly from one to three, carbon atoms, such as cycloalkyl-lower alkyl radicals, which contain from five to six carbon atoms as ring members, e.g. cyclopentylmethyl, l-cyclopentylethyl, 2-cyclopentylethyl, l-cyclopentylpropyl, 3-cyclopentylpropyl, cyclohexylmethyl, l-cyclohexylethyl, 2-cyclohexylethyl, l-cyclohexylpropyl, 3-cyclohexylpropyl and the like, or cycloalkenyl-lower alkyl radicals, which contain from five to six ring carbon atoms, e.g. 2-cyclopentenylmethyl, 3 cy-clopentenylmethyl, 1 (2 cyclopentenyl)- ethyl, l-(3-cyclopentenyl)-ethyl, 2 (2 cyclopentenyl)- ethyl, 2-(3-cyclopentenyl)-ethyl, 1-(2-cyclopentenyl)-propyl, 1-(S-cyclopentenyl)-propyl, 3 (2 cyclopentenyl)- propyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, l- (2-cyclohexenyl) -ethyl, 1- 3-cyclohexenyl) -ethyl, 2- 2- cyclohexenyl)-ethyl, 2-(3-cyclohexenyl)-ethyl, l-(2-cyclohexenyl)-propyl, l-(3-cyclohexenyl)-propyl, 3-(2-cyclohexenyl)-propyl, 3-(3-cyclohexenyl)-propyl and the like.

These aliphatic hydrocarbon radicals may contain additional substituents. Such substituents are primarily attached to lower alkyl radicals, which may be represented by a lower alkylene radical containing from one to five carbon atoms, such as for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,l-dimethyl-l,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,3-propylene, 2,2-propylene, 1,1-butylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 2,2-butylene, 2,3-butylene, 1,5-pentylene, 2,5-pentyl ene and the like.

Substituents are, for example, one or more than one halogen atom, e.g. fluorine, bromine, or particularly chlorine; halogeno-substituted lower alkyl radicals, representing R are, for example, chloromethyl, 2-chloroethyl, dichloromethyl, trichloromethyl, bromomethyl and the like. Other substituents are amino groups, such as primary amino groups, secondary amino groups, such as lower alkyl-amino, e.g. methylamino or ethylamino, carbocyclic aryl-amino, e.g. phenylamino, or carbocyclic aryl-lower alkyl-amino, e.g. benzylamino, or primarily tertiary amino groups, particularly N,N-di-lower :alkylamino, in whichlower alkyl has from one to seven carbon atoms, e.g. dimethylamino, N-ethyl-N-methyl-amino, diethylamino, dipropylamino, di-isopropylamino, dibutylamino and the like, N-cycloalkyl-N-lower alkyl amino, e.g. N-cyclopentyl-N-methyl-amino, N-cyclohexyl-N-methyl-amino and the like, N-carbocyclic aryl-lower alkyl-N-lower alkylamino, e.g. N-benzyl-N-methyl-amino, N-methyl-N-(Z- phenylethyl)-amino and the like, N,N-lower alkyleneimino group, in which the lower alkylene radical contains from four to six carbon atoms, such as pyrrolidino, e.g. pyrrolidino, Z-methyl-pyrrolidino and the like, piperidino, e.g. piperidino, Z-methyl-piperidino, 3-methyl-piperidino, 4-methyl-piperidino, 3-hydroxy-piperidino, 3-acetoxy-piperidino, 3-hydroxy-methyl-piperidino and the like, or hexamethylene-imino, N,N-lower oxa-alkylene-irnino, in which oxa-alkylene contains preferably four carbon atoms, e.g. morpholino and the like, or N,N-lower azaalkylene-imino, in which aza-alkylene contains preferably four carbon atoms, e.g. piperazino, 4-methyl-piperazino, 4-hydr-oxyethyl-piperazino, 4-acetoxyethyl-piperazino and the like. The tertiary amino group and the lower alkyl radical to which the amino group is attached may represent together a heterocyclic radical, in which the tertiary amino group is part of the heterocycle and one of the carbon atoms of the heterocyclic ring is connected directly or through a lower alkylene radical, e.g. methylene or 1,2-ethylene, with the 3-position of the 1,2,4-thiadiazine-1,1-dioxide portion. Such radicals are, for example, l-methyl-3 -piperidino-methy1, 2-( 1-methyl-2-piperidino ethylene, l-methyl-4-piperidino and the like.

Substituents attached to aliphatic hydrocarbon, particularly lower alkyl, radicals are also N-acylamino groups, in which acyl represents the acyl radical of an organic carboxylic acid, for example, a substituted carbonic acid,

e.g. methoxy-carbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, a lower aliphatic carboxylic acid, such as a lower alkanoic acid, e.g. acetic, propionic, pivalic acid and the like, lower alkanoic acids, e.g. acrylic, methylacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric, adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, particularly monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryllower aliphatic carboxylic acids, particularly monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryl-lower alkenyl carboxylic acids, e.g. cinnamic acid or substituted cinamic acids; substituents attached to these carboxylic acids are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g. dimethylamino, diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifiuoromethyl.

Acyl groups are additional substituents of aliphatic hydrocarbon, particularly lower alkyl, radicals, primarily acyl radicals of organic carboxylic acids, such as lower alkanoic acid, e.g. acetic, propionic, butyric acid and the like, as well as substituted carbonic acids, e.g. methoxycarbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, lower alkenoic acids, e.g. acrylic, methacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic succinic, glutaric, adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic iaryl-lower alkyl carboxylic acids, e.g. phenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryl-lower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnamic-acids. Additional substituents of these carboxylic acids are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as di-lower alkylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifiuoromethyl.

Other substituents attached to aliphatic hydrocarbon, particularly lower alkyl, radicals, are hydroxyl groups. Esterified hydroxyl groups may also be suitable as substituents, especially hydroxyl groups esterified by organic carboxylic acids, for example, substituted carbonic acids, e.g. methoxy-carbonic acid, ethoxy-carbonic acid, benzyloxy-carbonic acid and the like, lower aliphatic carboxylic acids, such as lower alkanoic acids, e.g. acetic, propionic, pivalic acid and the like, lower alkenoic acids, e.g. acrylic, methylacrylic acid and the like, lower aliphatic dicarboxylic acids, e.g. oxalic, malonic, succinic, glutaric adipic, maleic, fumaric acid and the like, or their halfesters with lower alkanols, e.g. methanol, ethanol and the like, carbocyclic aryl-carboxylic acids, primarily monocyclic carbocyclic aryl-carboxylic acids, e.g. benzoic or substituted benzoic acids, carbocyclic aryl-lower aliphatic carboxylic acids, primarily monocyclic carbocyclic aryl-lower alkyl carboxylic acids, e.g. phenylacetic, dihydrocinnamic acid and the like, which may contain additional substituents in the aromatic portion, or monocyclic carbocyclic aryl-lower alkenyl carboxylic acids, e.g. cinnamic acid and the like, or substituted cinnamic acids; substituents of such acids are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylcnedioxy, nitro, amino, particularly tertiary amino, such as di-lower alkyl-amino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl.

Further substituents of aliphatic hydrocarbon radicals, particularly lower alkyl radicals, are etherified hydroxyl groups, which may be represented, for example, by aliphatic hydrocarbonoxy, such as lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, lower alkenyloxy, e.g. vinyloxy, allyloxy and the like, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g. phenyloxy or substituted phenyloxy, or bicyclic carbocyclic aryloxy, e.g. l-naphthyloxy or Z-naphthyloxy or substituted naphthyloxy, or carbocyclic arylaliphatic hydrocarbonoxy, such as monocyclic carbocyclic aryl-lower alkoxy, e. g. benzyloxy or substituted benzyloxy. The aliphatic hydrocarbon, and particularly the carbocyclic aryl portions of the etherified hydroxyl groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, particularly tertiary amino, such as N,N-di-lower alkyl-amino, e.g. dimethylamino, diethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like or halogeno-lower alkyl, e.g. trifluoromethyl.

In addition, aliphatic hydrocarbon, particularly lower alkyl, radicals may be substituted by an etherified mercapto group, for example, aliphatic hydrocarbon-mercapto, such as lower alkyl-mercapto, methyl-mercapto, ethylmercapto, n-propyl-mercapto, isopropyl-mercapto, nbutyl-mercapto, isobutyl-mercapto and the like, lower alkenyl-mercapto, e.g. vinyl-mercapto, allyl-mercapto and the like, carbocyclic aryl mercapto, such as monocyclic carbocyclic aryl-mercapto, e.g. phenyl-mercapto or substituted phenyl-mercapto, or bicyclic carbocyclic aryl-mercapto, e.g. l-naphthyl-mercapto or Z-naphthyl-mercapto or substituted naphthyl-mercapto, or carbocyclic aryl-aliphatic hydrocarbon-mercapto, primarily monocyclic carbocyclic aryl-lower alkyl-mercapto, e.g. benzyl-mercapto, l-phenyl-ethyl-mercapto, 2-phenyl-ethyl-mercapto and the like, or substituted benzyl-mercapto, substituted l-phenylethyl-mercapto, substituted 2-phenyl-ethyl-mercapto and the like. The aliphatic hydrocarbon portions and, particularly, the carbocyclic aryl portions of the etherified mercapto groups may contain additional substituents; such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, nitro, amino, such as primary or secondary amines, or, particularly, tertiary amino, such as N,N-di-lower alkylamino, e.g. dimethylamino, diethylamino and the like, or N,N-lower alkylene-imino, e.g. pyrrolidino, piperidino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, halogeno-lower alkyl, e.g. trifluoromethyl. These substituents may be attached to any of the available positions; for example, monocyclic carbocyclic aryl radicals may be substituted in the ortho-, metaor para-positions, whereby one or more than one of the same or of dilferent substituents may be present.

Apart from aliphatic hydrocarbon radicals R may represent carbocyclic aryl groups, such as monocyclic carbocyclic aryl, e.g. phenyl or substituted phenyl, or bicyclic carbocyclic aryl, e.g. l-naphthyl or Z-naphthyl or substituted naphthyl radicals, or carbocyclic aryl-aliphatic hydrocarbon radicals, particularly monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-phenylethyl, 2- phenylethyl, 3-phenylpropyl, l-naphthylmethyl and the like or these radicals substituted in the carbocyclic aryl portion, or monocyclic or bicyclic carbocyclic aryl-lower alkenyl, e. g. 2-phenyl-ethenyl and the like, as well as such radicals containing in the carbocyclic portion additional substituents. Such substituents are, for example, lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, lower alkylenedioxy, e.g. methylenedioxy, lower alkyl mercapto, e.g. methylmercapto and the like, sulfamyl, amino, particularly tertiary amino, such as N,N-di-lower alkylamino, e.g. dimethylamino and the like, halogen, e.g. fluorine, chlorine, bromine and the like, or halogeno-lower alkyl, e.g. trifluoromethyl.

Additional groups representing R are heterocyclic aryl radicals, particularly monocyclic or bicyclic heterocyclic aryl radicals, such as pyridyl, e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl, thienyl, e.g. Z-thienyl, furyl, e.g. 2-furyl, or quinolyl, e.g. -6-quinolyl and the like or heterocyclic arylaliphatic hydrocarbon, such as monocyclic heterocyclicaryl-lower alkyl, for example, thenyl, e.g. 2-thenyl and the like. These radicals may contain additional substituents, particularly lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, or halogen, e.g. fluorine, chlorine, bromine and the like.

The radicals R R and R apart from being primarily hydrogen, may also represent lower aliphatic hydrocarbon radicals, such as lower alkyl, e.g. methyl, ethyl, propyl or isopropyl; monocyclic or bicyclic carbocyclic aryl, e.g. phenyl or 1- or Z-naphthyl; monocyclic or bicyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-naphthyl-methyl or 2-naphthyl-methyl; or these radicals containing substituents such as those specifically mentioned for the radical R substituted radicals are, for example, hydroxymethyl, hydroxyethyl or similar radicals.

The radical R stands primarily for halogen, e.g. fluorine, bromine, iodine or, particularly chlorine. In addition, it may also represent lower aliphatic hydrocarbon, for example, lower alkyl, e.g. methyl, ethyl and the like, or a substitued lower aliphatic hydrocarbon, such as a halogeno-lower alkyl radical, e.g. trifluoromethyl.

Salts of the diuretics which may be used in this invention are therapeutically useful salts with metals, particularly the alkali metal salts, such as those with sodium or potassium. Monoor poly-salts may be formed.

Diuretics, particularly useful in the invention, are the 3,4 dihydro 2-H-[1,2,4]-benzothiadiazine-l,l-dioxides of the formula: 1

in which R stands for hydrogen, lower alkyl, halogenolower alkyl, N,N-di-lower alkyl-amino-lower alkyl,lower alkanoyl-lower alkyl, lower alkoxy-lower alkyl, monocyclic carbocyclic aryloxy-lower alkyl, lower alkylmercaptolower alkyl, monocyclic arylmercapto-lower alkyl, monocyclic aryl-lower alkylmercapto-lower alkyl or monocyclic carbocyclic aryl-lower alkyl, R R and R represent hydrogen or lower alkyl, e.g. methyl, and R stands for halogen, particularly chlorine, lower alkyl, e.g. methyl, or halogeno-lowcr alkyl, e.g. trifluoromethyl. Representative of this group of compounds are the 3,4-dihydro-2-H- [1,2,4]-benzothiadiazine-l,l-dioxides of the formulae:

in which R stands for halogen, particularly chlorine,

in which R stands for lower alkyl or aryl-lower alkyl, and R represents halogen, particularly chlorine,

in which R stands for halogeno-lower alkyl, and R represents halogen, particularly chlorine or halogenolower alkyl, particularly trifluoromethyl, and

wherein R represents an'amino-lower alkyl radical, and R represents halogen, particularly chlorine,

wherein R represents hydroxy-lower alkyl, acyloxy-lower alkyl or etherified lower alkyl and R represents halogen, particularly chlorine,

wherein R represents a carbocyclic alicycle hydrocarbon radical or a carbocyclic alicyclic hydrocarbon-lower ali-' phatic hydrocarbon radical, and R represents halogen, particularly chlorine,

wherein R represents an etherified mercapto-lower alkyl group and R represents halogen, particularly chlorine,

wherein R represents a lower alkyl radical (e.-g. methyl, ethyl and the like) or a lower aralkyl radical (e. g. benzyl,

substituted benzyl, such as lower alkyl benzyl, lower alkoxy benzyl and the like) and R represents halogen, particularly chlorine or trifluoromethyl and the like.

Then benz-sulfamyl-3,4 dihydro 2-H-[1,2,4]-benzothiadiazine-1,1-dioxides used in this invention, in which the nitrogen atom of the sulfamyl group is unsubstituted or substituted, may be prepared by treating a benzsulfamyl-Z-sulfamyl-aniline compound, in which the nitrogen atoms of the sulfamyl groups may be unsubstituted or substituted, with an aldehyde. For example, the benz- N-R "'-sulfa.myl-2-R '-3 R -4 R "-3,4-dihydro 2-H- [1,2,4]-benzothiadiazone-1,l-dioxides, in which R R R .and R have the above-given meaning, and in which the carbocycli-c portion contains R of the above-given meaning as a further substi'tuent, the acylated derivatives and salts thereof, may be prepared by treating an aniline compound of the formula:

in which R R R and R have the above-given meaning, or a salt thereof, with an aldehyde of the formula R CHO, in which R has the above-given meaning and, if desired, replacing in any resulting 3,4-dihydro- 2 H-[1,2,41-benzothiadiazine 1,1 dioxide containing sulfamyl-nitrogen atoms with hydrogen, such hydrogen by hydrocarbon, and/or, if desired, converting a resulting 3,4-dihydro-2 H-[1,2,41-benzothiadiazine 1,1 dioxide into its ac-ylated derivative, and/or, if desired, converting a resulting salt into a free compound, and/or, if desired, converting a free compound into a salt thereof.

A salt of the aniline derivative used as the starting material may be a salt with an alkali metal or an acid addition salt. Preferably, the aldehyde is reacted with the aniline derivative in about stoichiometric amounts and in the presence of a small amount of an acid, particularly a mineral acid, such as hydro'halic acid, elg. hydrochlon'c or hydrobromic acid, or sulfuric acid, if desired, in anhydrous form. The aldehyde may also be given into the reaction medium in a form which yields the desired reactant in situ. Thus, for example, when formaldehyde is .used as the reactant, it may be desirable to use it in the form of a polymer, such as paraformaldehyde or trioxane, or as an acetal, such as dimethoxymethane or diethoxymethane. Other aldehydes may be used as acetals, such as 1,1-dimethoxy-ethane or 1,1-diethoxyethane. The reaction may be carried out in the absence or preferably in the presence of a solvent, for example, an ether, e.g. p-diox-ane or diethyleneglycol dimethylether, or a formamide,"e.g. dimethylformamide. It may be completed at an elevated temperature, for example, at the boiling temperature of the solvent. Thus, the aldehyde reactant is, for example, added to a preheated solution of the aniline derivative in the solvent containing the acid and heating may then 'be continued to complete the reaction. If necessary, the reaction may be performed under increased pressure or in the atmosphere of an inert gas, e.g. nitrogen.

Illustrating this generally applicable process is the treatment of a 5-R -2-(N-R '-sulfamyl)-4-(N-R '-sulfamyl)- N-R -aniline, in which R represents halogen, lower alkyl or halogeno-lower alkyl, and each of the radicals R R and R represents hydrogen or lower alkyl, with an aldehyde of the formula R CHO, in which R represents-hydrogen, lower alkyl, halogeno-lower alkyl, monocyclic carbocy clic aryl or monocyclic carbocyclic aryl-lower alkyl, in the presence of a small amount of a mineral acid, to form 2-R '-2-R -4-R "-6-R -7-(N-R sulfamyl -3,4-dihydro-2-H-[ 1,2,4] -benzothiadiazine 1,1- dioxide-s, in which R R R R and R have the above-given preferred meaning. For example, the 6-chloro-7-sulfamyl-3,4-dihydro-2-H-[1,2,4] benzothiadi-azine- 1,1-dioxide may be prepared by reacting 5-chloro-2,3-disulfamyl-aniline with an about equivalent amount of paraformaldehyde or aqueous formaldehyde in the presence of a small amount of hydrochloric acid.

. Standard sieve sizes.

More specifically, these compounds may be prepared as shown in the recited examples of'copending application Serial No. 764,482, of common assignment, two of which are given below:

Example A A mixture of 2.9 g. of -chloro-2,4-disulfamyl-aniline in 15 ml. of anhydrous diethyleneglycol dimethylether, 0.5 ml. of an ethyl acetate solution containing 109.5 g. of hydrogen chloride per 1000 ml. and 0.33 g. (0.011 mol) of paraformaldehyde is heated to 8090 C. and maintained at that temperature for one hour. The resulting mixture is cooled to room temperature and concentrated to one-third of its volume under reduced pressure, diluted with water, then allowed to crystallize. The product is filtered off and recrystallized from water, to yield the desired 6-chloro-7-sulfamyl-3 ,4-dihydro-2-H- 1 ,2,4] -benzothiadiazine-l,l-dioxide, M.P. 266268 C.; yield 1.4 g.

By replacing paraformaldehyde by 0.84 g. of 1,1-dimethoxymethane and proceeding as above, the same compound is obtained.

Example B A mixture of 2.9 g. of 5-chloro-2,4-disulfamyl-aniline in 20 ml. of anhydrous diethyleneglycol dimethylether, 0.44 g. of acetaldehyde and 0.5 ml. of a solution of hydrogen chloride in ethyl acetate (109.5 g. hydrogen chloride per 1000 ml.) is heated to 8090 C. and maintained at this temperature for one hour. The reaction mixture is concentrated under reduced pressure; on addition of water, the product separates and is then recrystallized from ethanol or aqueous ethanol to yield 1.2 g. of the desired 6-chloro-3-methyl-7-sulfamyl-3,4 dihydro 2 H- [1,2,4]-benzothiadiazine-l,l-dioxide, M.P. 258260 C.

The same product is obtained by replacing the acetaldehyde by 0.9 g. of 1,1-dimethoxyethane or by 1.2 g. of 1,1-diethoxyethane.

The preparation of additional hydrochlorothiazides and hydroflumethiazides useful in the invention is described in the working examples in deStevens et al. applications S.N. 764,482, filed September 29, 1958; S.N. 786,062, filed January 12, 1959; S.N. 788,782, filed January 26, 1959; S.N. 791,046, filed February 4, 1959; S.N. 791,045, filed February 4, 1959; and S.N. 791,044, filed February 4, 1959, all of which applications are now abandoned.

Following are working examples, illustrative of, but in no way intended to limit the present invention. Unless otherwise indicated, all parts, wherever given in the specification, are parts by weight. All sieve sizes are US.

Example 1 [10,000 tablets] Material and formula: Grams 6-chloro-3,4-dihydro-7-sulfamyl-2H 1,2,4- benzothiadiazine-l,l-dioxide (hydrochlorothiazide) 150.00 Reserpine 1.00 Lactose USP 1191.50 Acacia 75.00 Talc USP 75.00 Magnesium stearate USP 7.50 50% 3A alcohol, q.s.

Procedure for preparation.-Triturate the reserpine with 100 grams of lactose and force through a No. 50 screen. Incorporate the remainder of the lactose, the acacia and the hydrochlorothiazide. Granulate with sufficient 50% 3A alcohol. Pass the moist mass through a No. screen and dry with circulating air .at 110 F. until moisture content is 3 percent. Break the granules on a No. 16 screen and mix with the talc and magnesium stearate. Compress into tablets weighing 150 mg, using & inch punches and dies.

Example 2 [10,000 tablets] Material and formula: Grams 6-chloro-3,4-dihydro-7-sulfamyl-2H 1,2,4- benzothiadiazine-1,1-dioxide (hydrochlorothiazide) 250.00 Reserpine 2.50 Lactose USP 1165.40 Corn starch (anhydrous basis) 67.10 Stearic acid powder USP 15.00

Purified water, q.s.

Procedure for preparation.-Triturate the reserpine with grams of lactose. Pass the mixture through a No. 50 screen and combine with the hydrochlorothiazide, 38.5 grams of dry corn starch and the remainder of the lactose. Mix thoroughly. Suspend 28.6 grams of dry corn starch in 35 ml. of purified water and add m1. boiling purified water to form a paste. Granulate the mixed powders with this paste, using additional water if necessary. Pass the wet mass through a .No. 8 screen and dry at 100 F. with circulating air. Break the granules on a No. 14 screen and mix with the stearic acid powder. Compress into tablets weighing mg, using inch punches and dies.

Example 3 [10,000 tablets] Material and formula: Grams 6-chloro-3,4-dihydro-7-sulfamyl-2H 1,2,4- benzothiadiazine-l,l-dioxide (hydrochlorothiazide) 250.00 Reserpine triturate 5% 20.60 Lactose spray dried 1123.00 Corn starch (anhydrous basis) 67.10 Silicon dioxide (Cab-O-Sil) 30.00 Magnesium .stearate USP 9.00 D & C Brown No. 1 0.30

Purified water, q.s. 50% 3A anhydrous alcohol, q.s.

Procedure for preparati0n.Mix together the reserpine triturate 5%, the hydrochlorothiazide, silicon dioxide, magnesium stearate and 38.5 grams of dried corn starch. Dissolve the color in 35 ml. of purified water and suspend 28.6 mg. of dried corn starch in this solution. Make a paste by adding 140 ml. of purified water. Granulate the mixed powders with this paste, using sutficient 50% 3A alcohol to complete the granulation. Pass the moist mass through a No. 10 screen and dry with circulating air at 100 F. until moisture is 2 percent. Break the granules on a No. 14 screen and compress into tablets weighing 150 mg., using W 2 inch punches and dies.

Example 4 [10,000 tablets] Material and formula: Grams 6 chloro 3,4-dihydro-7-sulfamyl-2H-1,2,4-

benzothiadiazine-1,1-dioxide (hydrochlorothiazide) 250.00 Rescinnamine 5.00 Mannitol 66 7.50 Gelatin 20.00 Talc USP 50.00 Magnesium stearate USP 7.50

Purified water, q.s.

Procedure for preparation-Mix the rescinnamine with 50 grams of mannitol and force the mixture through a No. 50 screen. Mix the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in 130 ml. purified water, using heat. Granulate the hydrochlorothiazide-mannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 110 F.

until moisture content is less than 0.5%. Break the granules on a No. 16 screen and mix them with the talc, magnesium stearate and the rescinnamine-mannitol mixture. Compress into tablets weighing 100 mg., using inch punches and dies.

Example 5 [10,000 tablets] Material and formula:

Purified Water, q.s.

Procedure for preparati0n.--Mix the rescinnamine with 75 grams of mannitol and force through a No. 50 screen. Combine the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in 180 ml. purified Water, using heat. Granulate the hydrochlorothiazidemannitol mixture with the gelatin solution. Pass the moist mass through a No. screen and dry at 110 F. with circulating air until moisture content is less than 0.5 percent. Break the granules on a No. 14 screen and mix with the talc, magnesium stearate and the rescinnaminemannitol mixture. Compress into tablets weighing 150 mg., using inch punches and dies.

Example 6 [10,000 tablets] Material and formula: Grams 6 chloro 3,4-dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine-l,l-dioxide (hydrochlorothiazide) 125.00 Rescinnamine 5.00 Mannitol 790.00 Gelatin 20.00 Talc USP 50.00 Magnesium stearate 10.00

Purified water, q.s.

Procedure for preparati0n.-Mix the rescinnamine with 50 grams of mannitol and force the mixture through a No. 50 screen. Mix the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in. 130 ml. purified water, using heat. Granulate the hydrochlorothiazide-mannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 110 F. until moisture content is less than 0.5 percent. Break the granules on a No. 16 screen and mix them with the tale, magnesium stearate and the rescinnamine-mannitol mixture. Compress into tablets weighing 100 mg., using inch punches and dies.

Example 7 [10,000 tablets] 50% 3A alcohol, q.s.

Procedure for preparation.-Triturate the deserpidine with 100 grams of lactose and force through a No. 50 screen. Combine with the hydrochlorothiazide, tragacanth and the remainder of the lactose in a suitable 12 mixer and mix for 30 minutes. Granulate the mixed powders with sufficient 50% 3A alcohol. Pass the moist mass through a No. 10 screen and dry at F. with circulating air until moisture content is 3 percent. Break the granules on a No. 14 screen and mix with the corn starch, talc, and magnesium stearate. Compress into tablets weighing 150 mg., using V inch punches and dies.

Example 8 [10,000 tablets] Material and formula: Grams 6 chloro-3,4-dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine-1,1-dioxide (hydrochlorothiazide) 250.00 Deserpidine 2.50 Lactose spray dried 1232.50 Magnesium stearate USP 15.00

Procedure for preparation.Triturate the deserpidine with 100 grams of lactose and pass the mixture through a No. 50 screen. Combine with the hydrochlorothiazide, magnesium stearate and the remainder of the lactose in a suitable mixer and mix for 30 minutes. Compress into tablets Weighing 150 mg., using inch punches and dies.

Example 9 [10,000 tablets] Material and formula: Grams 6 chloro-3,4-dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine-1,1-dioxide (hydrochlorothiazide 500.00 Deserpidine 20.00 Lactose USP 1580.00 Sucrose USP 125.00 Corn starch 125.00 Talc USP 125.00 Magnesium stearate USP 25.00

Purified water, q.s.

Procedure for preparati0n.-Triturate the deserpidine with 300 grams of lactose and force through a No. 50 screen. Combine this material with the hydrochlorothiazide and the remainder of the lactose. Dissolve the sucrose in ml. of purified water, using heat. Granulate the mixed powders with the resultant syrup, using additional water if necessary. Pass the moist mass through a No. 8 screen and dry at 100 F. until moisture content is about 2 percent. Break the granules on a N0. 12 screen and mix with the corn starch, talc and mag- 50% A3 alcohol, q.s.

Procedure for preparati0n.-Triturate the reserpine with 100 grams of lactose and force through a No. '50 screen. Incorporate the remainder of the lactose, the acacia and the hydrochlorothiazide. Granulate with sufficient 50% 3A alcohol. Pass the moist mass through a No. 10 screen and dry with circulating air at 110 F. until moisture content is 3 percent. Break the granules on a No. 16 screen and mix with the talc and magnesium stearate. inch punches and dies.

Compress into tablets weighting mg., using Purified water, q.s.

Procedure for preparation.Triturate the reserpine with 100 grams of lactose. Pass the mixture through a No. 50 screen and combine with the hydrochlorothiazide, 38.5 grams of dry corn starch and the remainder of the lactose. Mix thoroughly. Suspend 28.6 grams of dry corn starch in 35 ml. of purified water and add 140 ml. boiling purified water to form a paste. Granulate the mixed powders with this paste, using additional water if necessary. Pass the Wet mass through :a No. 8 screen and dry at 100 F. with circulating air. Break the granules on a N0. 14 screen and mix with the stearic acid powder. Compress into tablets weighing 150 mg., using W inch punches and dies.

Example 12 [10,000 tablets] Material and formula:

6 chloro-3,4-dihydro-7-sulfarnyl-2Hi-1,2,4- benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 1000.00

Grams Purified water, q.s. 50% 3A anhydrous alcohol, q.s.

Procedure for prepanation.Mix together the reserpine triturate 5%, the hydrochlorothiazide, silicon dioxide, magnesium stearate and 38.5 grams of dried corn starch. Dissolve the color in 35 ml. of purified water and suspend 28.6 mg. of dried corn starch in this solution. Make a paste by adding 140 ml. of purified water. Granulate the mixed powders with this paste, using sufficient 50% 3A alcohol to complete the granulation. Pass the moist mass through a No. screen and dry with circulating air at 100 F. until moisture is 2 percent. Break the granules on a No. 14 screen and compress into tablets weighing 150 mg., using inch punches and dies.

Example 13 [10,000 tablets] Material and formula: Grams 6 chloro 3,4 dihydro-7-sulfamyl-2H-1,2,4-

benzothiadiazine-1,1-dioxide (hydrochlorothiazide) 500.00 Rescinnamine 50.00 Mannitol "L 372.50 Gelatin 20.00 Talc USP 50.00 Magnesium stearate USP 7.50

Purified water, q.s.

Procedure for preparation.-Mix the rescinnamine with 50 grams of mannitol and force the mixture through -a No. 50 screen. Mix the remainder of the mannitol with the hydrochlorothiazide. Dissolve the igelatine in 130 ml. purified water, using heat. Granulate the hydrochlorothiazide-mannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 110 F. until moisture content is less than 0.5 percent.

. 14 Break the granules on a No. 16 screen and mix them with the talc, magnesium stearate and the rescinnaminemannitol mixture. Compress into tablets weighing mg., using inch punches and dies.

Example 14 [10,000 tablets] Material and formula: Grams 6 chloro-3,4-dihydro-7-sulfamy1-2H1,2,4-

benzothiadiazine 1,1 dioxide (hydrochlorothiazide) 1000.00 Rescinnamine 25.00 Mannitol 355.00 Gelatin 30.00 Talc USP 75.00 Magnesium stearate USP 15 .00

Purified water, q.s.

' moist mass through a No. 10 screen and dry at F.

with circulating air until moisture content is less than 0.5 percent. Break the granules on a No. 14 screen and mix with the tale, magnesium stearate and the rescinnamine-mannitol mixture. Compress into tablets weighing 150 -mg., using inch punches and dies.

Example 15 [10,000 tablets] Material and formula: Grams -6 chloro 3,4 dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine-1,1-dioxide (hydrochlorothiazide) '25 0.00 Rescinnamine 50.00 Mannitol 620.00 Gelatin 20.00 Talc USP 50.00 Magnesium stearate USP 10.00

Purified water, q.s.

Procedure for preparution.Mix the rescinnarnine with 50 grams of mannitol and force the mixture through a No. 50 screen. Mix the remainder of the mannitol with the hydrochlorothiazide. Dissolve the gelatin in ml. purified water, using heat. Granulate the hydrochlorothiazide-mannitol mixture with the gelatin solution. Pass the moist mass through a No. 10 screen and dry at 100 F. until moisture content is less than 0.5 percent. Break the granules on a No. 16 screen and mix them with the talc, magnesium stearate and the rescinnaminemannitol mixture. "Compress into tablets weighing 100 mg., using inch punches and dies.

Example 16 [10,000 tablets] Material and formula: Grams 6 chloro 3,4 dihydro-7-sulfamyl-2H-1,2,4- benzothiadiazine-1,1-dioxide (hydrochlorothiazide) 500.00 Deserpidine 0.50 Lactose spray dried 842.00 Tragacanth USP 30.00 Corn starch 75.00 Talc USP 45.00 Magnesium stearate USP 7 .50

50% 3Aalcohol, q.s.

Procedure for preparation.-Triturate the deserpidine with 100 grams of lactose and force through a No. 50 screen. Combine with the hydrocholorothiazide, tragacanth and the remainder of the lactose in a suitable mixer and mix for 30 minutes. .Granulate the mixed powders 'lating air until moisture content is 3 percent.

15 with sufiicient 50% 3A alcohol. Pass the moist mass through a No. 10 screen and dry at 100 F. with circu- Break the granules on a No. 14 screen and mix with the corn starch, talc, and magnesium stearate. Compress into tablets weighing 150 mg, using inch punches and dies.

Example 17 [10,000 tablets] Purified Water, q.s

Procedure for preparation.Triturate the deserpidine with 300 grams of lactose and force through a No. 50 screen. Combine this material with the hydrochlorothiazide and the remainder of the lactose. Dissolve the sucrose in 125 ml. of purified water, using heat. Granulate the mixed powders with the resultant syrup, using additional water if necessary. Pass the moist mass through a No. 8 screen and dry at 100 F.'until moisture content is about 2 percent. Break the granules on a No. 12 screen and mix with the corn starch, talc and magnesium stearate. Compress into tablets weighing 250 mg, using 11/32 inch punches and dies.

Example 18 [10,000 tablets] Material and formula: .Grams 6-chloro-3,4-dihydro-7-sulfamyl-2H- 1,2,4-benzothiadiazine-1,l-dioxide (hydrochlorothiazide) 1000.00 Deserpidine 2.50 Lactose spray dn'ed 482.50 Magnesium stearate USP 15.00

Procedure for preparatin.Triturate the deserpidine with 100 grams of lactose and pass the mixture through a No. 50 screen. Combine with the hydrochlorothiazide, magnesium stearate and the remainder of the lactose in a suitable mixer and mix for 30 minutes. Compress into tablets weighing 150 mg, using 9/32 inch punches and dies.

One may substitute any other dihydro benzothiadiazine-1,1-dioxide diuretic, in equivalent amount, for the diuretic given in the examples above, to obtain analogous compositions. Thus, among the diuretics which may be substituted are 6-chloro-3,4-dihydro-2-ethyl(or benzyl or alkyl)-7-sulfamyl 1,2,4 benzothiadiazine-l,l-dioxide; 6- chloro-3,4-dihydro-3-dichloromethyl 7 sulfamyl-1,2,4- thiadiazine-1,1-dioxide, etc.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A pharmaceutical composition, in oral dosage unit form, comprising about 1 to about 20 percent of a compound of the formula in which R is a member selected from the group consisting of; hydrogen, lower alkyl, halogeno-lower alkyl, phenyl, naphthyl, phenyl-lower alkyl, and naphthyl-lower alkyl, R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentyl-lower alkyl, cyclopentenyl-lower alkyl, cyclohexyl-lower alkyl and cyclohexenyl-lower alkyl, at least one of the substituents R and R being other than hydrogen and R is a member selected from the group consisting of halogen, and halogeno-lower alkyl and about .01 to about 0.04 percent indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

2. A pharmaceutical composition, in oral dosage unit form, comprising about 2.5 to about 10 percent of a compound of the formula in which R is a member selected from the group consisting of hydrogen, lower alkyl, halogeno-lower alkyl, phenyl, naphthyl, phenyl-lower alkyl, and naphthyl-lower alkyl, R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cy-

' clopentyl-lower alkyl, cyclopentenyl-lower alkyl, cyclohexyl-l-ower alkyl and cyclohexenyl-lower alkyl, at least one of the substituents R and R being other than hydrogen and R is a member selected from the group consisting of halogen, and halogeno-lower alkyl and about .01 to about 0.04 percent indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

3. A pharmaceutical composition, in oral dosage unit form, comprising about 2.5 percent of a compound of the formula in which R is a member selected from the group consisting of hydrogen, lower alkyl, halogeno-lower alkyl, phenyl, naphthyl, phenyl-lower alkyl, and naphthyl-lower alkyl, R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclopentyl-lower alkyl, cyclopentenyl-lower alkyl, cyclohexyl-lower alkyl and cyclohexenyl-lower alkyl, at least one of the substituents R and R being other than hydrogen and R is a member selected from the group consisting of halogen, and halogeno-lower alkyl and about .01 percent indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

4. A pharmaceutical composition, in oral dosage unit form, comprising about 10 to about 200 milligrams of a compound of the formula n and R; is a member selected from the group consisting of halogen, and halogeno-lower alkyl and about 0.10 to about 0.4 milligram indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

5. A composition of claim 1 wherein R is trifluoromethyl.

6. A composition of claim 1 wherein R is chloro.

7. A pharmaceutical composition, in oral dosage unit form, comprising about 25 to about 100 milligrams of 6- trifluoro-methyl 7 sulfamyl 3,4 dihydro-2-H-[1,2,4]- benzothiadiazine-1,1-dioxide and about 0.1 to about 0.4 milligram indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

8. A pharmaceutical composition, in oral dosage unit form, comprising about 10 to about 200 milligrams of 3- lower alkyl-6-chloro-7-sulfamyl-3,4-dihydro-2-H [1,2,4]- benzothiadiazine-l,l-dioxide and about 0.05 to about 5.0 milligrams indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

9. A pharmaceutical composition, in oral dosage unit form, comprising about 25 to about 100 milligrams of 3-phenyl lower alkyl-6-chloro-7-sulfamyl-3,4-dihydro-2- H-[1,2,4]-benzothiadiazine-1,l-dioxide and about 0.05 to about 5.0 milligrams indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

10. A pharmaceutical composition, in oral dosage unit form, comprising about 25 milligrams of 3-R -6-chloro-7- sulfamyl-3,4-dihydro-2-H-[1,2,4]-benzothiadiazine 1,1 dioxide wherein R is a member selected from the group consisting of lower alkyl and phenyl-lowe'r alkyl and about 0.1 to about 0.5 milligram of indole alkaloid of the Apocynaceae family selected from the group consisting of reserpine, deserpidine and rescinnamine.

References Cited by the Examiner JULIAN S. LEVITT, Primary Examiner.

LEROY B. RANDALL, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,288,678 November 29, 1966 George de Stevens et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 16 lines 2 25 48 and 71 beginning with "cyclopentyl" strike out all to and including "cyclohexenyl-lower alkyl" in lines 4, 27, 49 and 73, each occurrencejand insert the same after "alkyl," in column 15, line 74, and column 16, lines 22,

45 and 68; column 16, lines 1, 24, 47 and 70, for "alkenyl,", each occurrence, read alkenyl and Signed and sealed this 20th day of August 1968.

(SEAL) Attest:

Edward M. Fletcher, Jr. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A PHARMACEUTICAL COMPOSITION, IN ORAL DOSAGE UNIT FORM, COMPRISING ABOUT 1 TO ABOUT 20 PERCENT OF A COMPOUND OF THE FORMULA 